Programmable Lithium-Ion Delivery Devices for Motor-Sparing Neuropathic Pain Therapy - Project Summary Neuropathic pain is a debilitating condition caused by aberrant peripheral afferent activity and central sensitization, with few durable or motor-sparing treatment options. Current interventions—including systemic drugs and implanted electrical stimulators—are constrained by poor spatial selectivity, systemic toxicity, and progressive long-term instability. This project introduces a fundamentally new strategy: a lithium-delivering bioelectronic platform with AI-enabled closed-loop control that provides programmable, localized, and reversible conduction block. The core innovation is the repurposing of lithium iron phosphate (LFP), a crystalline mineral cathode from energy storage, as a biocompatible and electrochemically stable source of lithium ions for neuromodulation. Unlike systemic lithium therapy, which requires toxic plasma concentrations, or electrical stimulators, which induce fibrosis and impedance drift, this approach achieves epineurial, spatially confined Li⁺ release with high Faradaic efficiency, tunable dosing, and chronic stability. Integrated with wearable sensors and edge-AI algorithms, the system enables real-time detection of pain-linked signatures and adaptive lithium release, producing a responsive neuromodulation platform. The research is organized into four integrated aims. Aim 1 will synthesize LFP nano- and microparticles and fabricate flexible cuff and injectable electrodes using Cathode Materials Photolithography. Morphology tuning and kirigami-inspired geometries will enhance lithium diffusion and conformity, while electrochemical and mechanical benchmarking will ensure dosing precision and durability. Aim 2 will evaluate device biocompatibility and bio-stability through neuronal cultures, iPSC-derived networks, organotypic explants, and staged in vivo studies in spared-nerve-injury mice and peroneal nerve injury sheep. Aim 3 will define the mechanism of lithium- mediated inhibition using patch-clamp electrophysiology, calcium imaging, and multi-omics analyses. These studies will test how Li⁺ engages Na⁺/K⁺ ATPase and Na⁺/Ca2⁺ exchangers to suppress excitability while sparing motor function, and will map downstream suppression of adenylate cyclase–cAMP signaling with proteomics, biosensors, and super-resolution imaging. Aim 4 will establish in vivo neuromodulation efficacy, beginning with spared-nerve-injury mice for electrophysiological and behavioral validation, and advancing to sheep with fully implantable wireless systems. Closed-loop Tiny Machine Learning (TinyML) algorithms, wearable biosensors, and ultrasound-guided placement will demonstrate motor-sparing analgesia during natural ambulation. By uniting Tian's expertise in materials science and flexible bioelectronics, Niu's innovations in adaptive AI, and Kohane's leadership in translational physiology, this project establishes a new paradigm for neuromodulation: precise, reversible, and durable ion-based inhibition under adaptive closed-loop control. If successful, it will deliver a clinically translatable lithium bioelectronic therapy for neuropathic pain, with broad potential to transform the treatment of neurological disorders and lay the foundation for future intelligent neuromodulation platforms.
